The familial dementia BRI2 gene binds the Alzheimer gene amyloid-β precursor protein and inhibits amyloid-β production

Alzheimer disease (AD), the most common senile dementia, is characterized by amyloid plaques, vascular amyloid, neurofibrillary tangles, and progressive neurodegeneration. Amyloid is mainly composed by amyloid-beta (A beta) peptides, which are derive from processing of the beta-amyloid precursor protein (APP), better named amyloid-beta precursor protein (A beta PP), by secretases. The (A) under bar beta PP intracellular domain (AID), which is released together with A beta, has signaling function, since it modulates apoptosis and transcription. Despite its biological and pathological importance, the mechanisms regulating A beta PP processing are poorly understood. As cleavage of other gamma-secretase substrates is regulated by membrane bound proteins, we have postulated the existence of integral membrane proteins that bind A beta PP and regulate its processing. Here, we show that BRI2, a type II membrane protein, interacts with A beta PP. Interestingly, 17 amino acids corresponding to the NH2-terminal portion of A beta are necessary for this interaction. Moreover, BRI2 expression regulates A beta PP processing resulting in reduced A beta and AID levels. Altogether, these findings characterize the BRI2-A beta PP interaction as a regulatory mechanism of A beta PP processing that inhibits A beta production. Notably, BRI2 mutations cause familial British (FBD) and Danish dementias (FDD) that are clinically and pathologically similar to AD. Finding that BRI2 pathogenic mutations alter the regulatory function of BRI2 on A beta PP processing would define dysregulation of A beta PP cleavage as a pathogenic mechanism common to AD, FDD, and FBD.